The IL-6-Soluble IL-6Rα Autocrine Loop of Endothelial Activation as an Intermediate Between Acute and Chronic Inflammation: an Experimental Model Involving Thrombin

Marin, Valérie; Montero‐Julian, Félix A.; Grès, Sandra; Boulay, Véra; Bongrand, Pierre; Farnarier, Catherine; Kaplanski, Gilles

doi:10.4049/jimmunol.167.6.3435

Cited by 195 publications

(169 citation statements)

References 51 publications

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“…31,36 The studies outlined herein highlight that regulation of IL6 transsignaling relies primarily on the initial influx of neutrophils, which has been shown in vitro to shed IL6R in response to inflammatory chemokines, lipid mediators, complement components, C-reactive protein, and neutrophil apoptosis. 13,27,36,[45][46][47] The subsequent appraisal of leukocyte recruitment and inflammatory chemokine expression in opt_sgp130Fc transgenic mice showed that IL6 transsignaling was responsible for triggering the chemokine-mediated recruitment of mononuclear phagocytes. Indeed, the over-expression of sgp130Fc led to impaired expression of the inflammatory chemokine MCP-1/ CCL2.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, endothelial cells, which secrete inflammatory chemokines, only express the gp130 signal transducing chain but not the IL6-specific IL6R. 31,36 In an experimental peritonitis model, the induction of MCP-1 on mesothelial cells can be induced by injection of Hyper-IL6 into the peritoneum of IL6 Ϫ/Ϫ mice. 13 We therefore asked whether the infiltration of mononuclear cells in vivo relies on IL6 transsignaling by specifically blocking IL6 transsignaling.…”

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confidence: 99%

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Transgenic blockade of interleukin 6 transsignaling abrogates inflammation

Rabe

Chalaris

May

et al. 2008

Blood

230

208

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IntroductionIL6 has major functions in inflammatory reactions of the body. 1,2 Mice with a targeted inactivation of the IL6 gene are completely protected in animal models of rheumatoid arthritis 3,4 and multiple sclerosis. 5 Furthermore, regenerative reactions such as wound healing and liver regeneration are severely compromised in IL6 Ϫ/Ϫ mice. 6 A soluble form of the IL6R can bind IL6 with the same affinity as the membrane-bound form and the complex of IL6 and the soluble IL6R (sIL6R) can induce signaling in a process called IL6 transsignaling. 7,8 Because the IL6R is only sparely expressed, IL6 transsignaling dramatically increases the number of potential IL6 target cells. 9 This is relevant for inflammatory processes in vivo, because endothelial cells and smooth muscle cells, which play key roles in inflammation, lack IL6R expression. The interest in the role of IL6 in inflammatory processes has recently been intensified by the finding that the differentiation of TH 17 cells, which is a prerequisite for inflammatory damage during autoimmune disease, shows a dependence on IL6 in combination with TGF␤. 10 Recent studies with animal models of inflammatory bowel disease, 11,12 peritonitis, 13 rheumatoid arthritis, 14,15 and inflammatory colon cancer 16 suggest that IL6 transsignaling serves as the major proinflammatory paradigm of IL6 signaling under pathophysiologic conditions.To further analyze the relevance of IL6-transsignaling in vivo we generated a mouse model in which IL6-transsignaling is specifically abrogated. There have been reports describing the generation of knock-in mice with noncleavable L-selectin and noncleavable TNF-␣, showing that shedding of membrane proteins was important for antigen-stimulated lymphocyte migration and for secondary lymphoid organ architecture. 17,18 Such a strategy is impractical in the case of the sIL6R because its generation is complex and can be generated by ectodomain shedding as well as by translation from an alternatively spliced mRNA. Furthermore, shedding of the IL6R was also shown to occur at multiple cleavage sites and performed by multiple and distinct sheddase activities. [19][20][21][22] We therefore decided to generate transgenic mice overexpressing the sgp130Fc-protein that had been demonstrated to completely block IL6 transsignaling without affecting activities via the membrane bound IL6R. Blocking of IL6 transsignaling via sgp130Fc is independent of the mode of sIL6R generation. The need for a large molar excess of the sgp130Fc-protein necessitated the development of a codon optimization strategy that should be relevant for the construction of all animal models, which are based on the overexpression of heterologous proteins.The data presented here clearly show that sgp130Fc transgenic mice display an IL6-transsignaling knockout-like phenotype and establish them as the only possible in vivo model of this IL6-transsignaling paradigm. Here, we demonstrate in the air-pouch model of inflammatory activation that the transition from the neutrophil-dominated phase...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Transgenic blockade of interleukin 6 transsignaling abrogates inflammation

Rabe

Chalaris

May

et al. 2008

Blood

230

208

View full text Add to dashboard Cite

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“…The transition from PMN to mononuclear cell infiltration can be explained by enhanced clearance of PMNs and the induction of the mononuclear cell chemokine monocyte chemotactic protein 1 by the endothelium after stimulation with the IL-6/sIL-6R␣ complex (25,26). However, after the first week of joint inflammation, PMNs were still present in WT mice but absent in IL-6 Ϫ/Ϫ mice, and this suggests a protective effect of IL-6 on PMN survival.…”

Section: Discussionmentioning

confidence: 99%

Local activation of STAT‐1 and STAT‐3 in the inflamed synovium during zymosan‐induced arthritis: Exacerbation of joint inflammation in STAT‐1 gene–knockout mice

Hooge¹,

Loo²,

Koenders³

et al. 2004

Arthritis & Rheumatism

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Objective. STAT proteins play an important role in cytokine signaling. Some investigators have reported preferential activation of STAT-1, and others have reported preferential activation of STAT-3, in response to endogenous interleukin-6 (IL-6), in patients with rheumatoid arthritis. The present study was undertaken to investigate synovial STAT-1 and STAT-3 activation in an experimental animal model of arthritis.Methods. Zymosan was injected intraarticularly into naive wild-type (WT), IL-6 ؊/؊ , and STAT-1 ؊/؊ mice to induce arthritis. Western blots of synovial lysates were probed with phosphospecific antibodies to detect STAT-1/STAT-3 activation. Inflammation was assessed histologically. Synovial gene expression of the STATinduced feedback inhibitors suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 in WT and STAT-1 ؊/؊ mice was investigated by reverse transcriptasepolymerase chain reaction.Results. STAT-3 was activated in inflamed synovium of WT mice throughout the course of disease, whereas activated STAT-1 was observed only during the chronic phase. In IL-6 ؊/؊ mice, STAT activation was limited to STAT-3 on day 1. Although macrophage influx was not inhibited, disease went into remission after day 7 in IL-6 ؊/؊ mice. STAT-1 deficiency resulted in exacerbation of chronic joint inflammation and granuloma formation. In STAT-1 ؊/؊ mice, STAT-3 activation in the inflamed joints was unaltered as compared with WT mice. However, synovial SOCS-1, but not SOCS-3, gene expression was markedly reduced in STAT-1 ؊/؊ mice.Conclusion. The results in the IL-6 ؊/؊ mice suggest that STAT-3 is involved in the chronicity of ZIA. Exacerbation of arthritis in STAT-1 ؊/؊ mice suggests an opposing effect of STAT-1, i.e., suppression of joint inflammation. The expression of SOCS-1 could be the underlying mechanism by which STAT-1 controls joint inflammation.

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“…26 A subsequent monocyte/macrophage influx promotes chronic inflammation. 27 In preparations of highly purified circulating leukocyte subtypes, macrophages, but not neutrophils, produced the Th1 cytokines, TNF-␣, and IL-1␤. By contrast, only neutrophils produced Th2 mediators, such as the cytokine inhibitors TNF soluble receptor type 2 and the IL-1 receptor antagonist, 28 suggesting that neutrophils can protect against chronic inflammation and its potential pathological consequences.…”

Section: Discussionmentioning

confidence: 99%

“…By contrast, only neutrophils produced Th2 mediators, such as the cytokine inhibitors TNF soluble receptor type 2 and the IL-1 receptor antagonist, 28 suggesting that neutrophils can protect against chronic inflammation and its potential pathological consequences. 27 Leukocytes traffic into inflammatory sites by migrating down a chemotactic gradient then interacting with endothelial cell-expressed adhesion molecules. 29 Driving this process are members of the CXC chemokine superfamily, including IL-8, ENA-78, GRO-␣, and GCP-2.…”

Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor-α and Interleukin-1β Regulate Interleukin-8 Expression in Third Trimester Decidual Cells

Lockwood

Arcuri

Toti

et al. 2006

The American Journal of Pathology

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Chorioamnionitis is associated with intense neutrophil infiltration of the decidua. We therefore determined whether chorioamnionitis enhances decidual interleukin-8 (IL-8) expression and examined cytokine-regulated decidual IL-8 expression. Decidua from chorioamnionitis-complicated pregnancies, but not term controls, displayed marked IL-8 immunohistochemical staining and a dense neutrophil infiltrate.

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The IL-6-Soluble IL-6Rα Autocrine Loop of Endothelial Activation as an Intermediate Between Acute and Chronic Inflammation: an Experimental Model Involving Thrombin

Cited by 195 publications

References 51 publications

Transgenic blockade of interleukin 6 transsignaling abrogates inflammation

Transgenic blockade of interleukin 6 transsignaling abrogates inflammation

Local activation of STAT‐1 and STAT‐3 in the inflamed synovium during zymosan‐induced arthritis: Exacerbation of joint inflammation in STAT‐1 gene–knockout mice

Tumor Necrosis Factor-α and Interleukin-1β Regulate Interleukin-8 Expression in Third Trimester Decidual Cells

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